Abstract
目的
副肿瘤性天疱疮合并实体肿瘤的重症患者通常需要在手术后收住重症医学科(intensive care unit，ICU)治疗，这类患者的长期死亡率较高。本研究对这类患者的临床特点及远期预后的影响因素进行分析。
方法
回顾性分析2005年1月至2020年12月间63例副肿瘤性天疱疮合并实体肿瘤、手术后收住ICU重症患者的临床和实验室资料，并对患者的生存状况进行随访。
结果
63例患者中，原发肿瘤为Castleman病的占79.4%，其他病理类型为20.6%；皮损程度在重度-广泛的占69.8%，其他皮损程度占30.2%；合并闭塞性细支气管炎的占44.4%，不合并的占55.6%。23.8%的患者并发术后真菌感染，无真菌感染占76.2%。术后中位随访时间为95个月，25例患者在研究期间死亡，术后1年、3年、5年生存率分别为74.6%(95%CI 63.8%~85.4%)、67.4%(95%CI 55.6%~79.2%)和55.1%(95%CI 47.9%~62.3%)。通过对分类因素采用Log-rank法进行单因素分析结果表明：年龄＞40岁(P=0.042)、发病后体质量下降＞5 kg(P=0.002)、术前白蛋白 < 30 g/L(P < 0.001)、并发闭塞性细支气管炎(P=0.002)、围术期存在真菌感染(P＜0.001)的患者死亡率增加；Cox单因素分析显示术前体质量下降>5 kg(P=0.005)、术前白蛋白 < 30 g/L(P < 0.001)、术前合并闭塞性细支气管炎(P=0.009)、术前肺部细菌感染(P=0.007)、手术时间长(P=0.048)、术后入ICU时氧合指数(P=0.012)和白蛋白(P=0.010)、血红蛋白浓度低(P=0.035)、入ICU后急性生理学及慢性健康状态评分(acute physiology and chronic health evaluation, APACHE Ⅱ, P=0.001)、序贯器官衰竭评分(sequential organ failure assessment, SOFA, P=0.010)，以及术后真菌感染都是影响远期存活的危险因素(P < 0.001)。Cox回归模型进行多因素分析结果表明，术前体质量下降＞5 kg(HR 4.44; 95%CI 1.47~13.38; P=0.008)、术前白蛋白 < 30 g/L(HR 4.38; 95%CI 1.72~11.12; P=0.002)、术前合并闭塞性细支气管炎(HR 2.69; 95%CI 1.12~6.50; P=0.027)及术后并发真菌感染(HR 4.85; 95%CI 2.01-11.72; P＜0.001)是术后死亡的独立危险因素。
结论
因副肿瘤性天疱疮合并实体肿瘤而接受手术治疗的重症患者术后的5年存活率约为55.1%，术前体质量下降＞5 kg、白蛋白 < 30 g/L、合并闭塞性细支气管炎和术后并发真菌感染是术后近远期死亡风险增加的影响因素。
Keywords: 副肿瘤性天疱疮, Castleman病, 闭塞性细支气管炎
Abstract
Objective
Critically ill patients with solid tumors complicated with paraneoplastic pemphigus are usually treated in intensive care units (ICU) for perioperative management after surgical treatment. In this study, the clinical characteristics and predictors of long-term prognosis of these critically ill patients were analyzed.
Methods
the clinical and laboratory data of 63 patients with solid tumors complicated with paraneoplastic pemphigus admitted to ICU from 2005 to 2020 were retrospectively analyzed, and the survival status of the patients were followed up.
Results
Among the 63 patients, 79.4% had Castleman disease as the primary tumor, and 20.6% with other pathological types; 69.8% had severe-extensive skin lesions, and 30.2% had other skin lesions; the patients with bronchiolitis obliterans accounted for 44.4%, and 55.6% were not merged. Postoperative fungal infection occurred in 23.8% of the patients, and 76.2% without fungal infection. The median follow-up time was 95 months, and 25 patients died during the study period. The 1-year, 3-year and 5-year survival rates were 74.6% (95%CI 63.8%-85.4%), 67.4% (95%CI 55.6%-79.2%) and 55.1% (95%CI 47.9%-62.3%), respectively. The log-rank univariate analysis showed that the patients had age>40 years (P=0.042), preoperative weight loss>5 kg (P=0.002), preoperative albumin < 30 g/L (P < 0.001), paraneoplastic pemphigus complicated with bronchiolitis obliterans (P=0.002), and perioperative fungal infection (P < 0.001) had increased mortality. Cox univariate analysis showed that preoperative weight loss >5 kg (P=0.005), preoperative albumin < 30 g/L (P < 0.001), paraneoplastic pemphigus complicated with bronchiolitis obliterans (P=0.009), preoperative bacterial pulmonary infection (P=0.007), prolonged surgical time (P=0.048), postoperative oxygenation index (P=0.012) and low albumin (P=0.010) and hemoglobin concentration (P=0.035) in ICU, acute physiology and chronic health evaluation (APACHE Ⅱ) score (P=0.001); sequential organ failure assessment (SOFA) score (P=0.010), and postoperative fungal infection (P < 0.001) were risk factors for long-term survival. Cox regression model for multivariate analysis showed that preoperative weight loss > 5 kg (HR 4.44; 95%CI 1.47-13.38; P=0.008), and preoperative albumin < 30 g/L (HR 4.38; 95%CI 1.72-11.12; P=0.002), bronchiolitis obliterans (HR 2.69; 95%CI 1.12-6.50; P=0.027), and postoperative fungal infection (HR 4.85; 95%CI 2.01-11.72; P < 0.001) were independent risk factors for postoperative mortality.
Conclusion
The 5-year survival rate of critically ill patients undergoing surgery for paraneoplastic pemphigus combined with solid tumors is approximately 55.1%, with preoperative weight loss > 5 kg, albumin < 30 g/L, bronchiolitis obliterans and postoperative fungal infection were associated with an increased risk of near- and long-term postoperative mortality.
Keywords: Paraneoplastic pemphigus, Castleman disease, Bronchiolitis obliterans
副肿瘤性天疱疮最早在1990年由Anhalt等[1]报道，是一种罕见的自身免疫性疾病，表现为致命性的黏膜和皮肤的大疱性疾病，可影响多个系统的功能[2]。副肿瘤性天疱疮占所有天疱疮的3%~5%[3]，是一种伴发于肿瘤的特殊类型的天疱疮，常合并源于淋巴系统的肿瘤，例如非何杰金淋巴瘤、慢性淋巴细胞性白血病、Castleman病、胸腺瘤等[1]。
由于副肿瘤性天疱疮会对全身多个系统器官造成影响，患者常出现预后不佳，既往文献报道的副肿瘤性天疱疮的死亡率可高达50%~90%[4-5]。导致副肿瘤性天疱疮患者住院及死亡的相关危险因素包括皮损形态、部位，皮肤和肺部感染，病程时长和肿瘤性质，以及治疗手段如激素、免疫抑制剂、丙种球蛋白、手术和化疗等[6]。副肿瘤性天疱疮的病情进展和其相伴的肿瘤不是平行发展的[3, 7]，在肿瘤化疗甚至切除后，皮疹和肺部病变仍可进一步恶化[8]。超过90%的副肿瘤性天疱疮病例伴随有累及呼吸道上皮的病变，临床表现为呼吸困难、阻塞性肺病和闭塞性细支气管炎，是副肿瘤性天疱疮的主要死亡原因之一[9]。文献报道63%以上的闭塞性细支气管炎患者5年内死于呼吸衰竭[10]，但是对于手术切除副肿瘤性天疱疮相关肿瘤后而入住重症医学科(intensive care unit，ICU)的危重患者，目前还缺乏临床特点的总结和长期预后的研究。
本研究回顾性分析了手术切除副肿瘤性天疱疮相关肿瘤后入住ICU患者的临床特征和远期结局，并分析了影响远期预后的因素。
1. 资料与方法
1.1. 研究对象
本研究为回顾性队列研究，研究方案已获北京大学第一医院生物医学研究伦理委员会批准(2022-058)，并申请免知情同意签署。选择于2005年1月1日至2020年12月31日期间，因副肿瘤性天疱疮合并实体肿瘤而行肿瘤切除手术、围术期收住ICU的患者。所有入组患者及家属均在电话随访中被告知本研究的情况，并口头同意信息采集。本研究符合观察性研究报告规范。
1.2. 纳入和排除标准
纳入标准：在皮科确诊为副肿瘤性天疱疮，通过影像学明确肿瘤存在和位置，转入外科行手术治疗；术前皮肤或黏膜病变活检的组织学结果或术后的病理检查证实副肿瘤性天疱疮诊断；围手术期收入ICU。排除标准：术后病理检查结果证实非副肿瘤性天疱疮；患者或家属不同意进入研究队列；手术未切除肿物。
1.3. 围术期管理
患者在收入外科准备行手术后，术前完善各项检查及副肿瘤性天疱疮相关并发症的诊断。维持针对皮疹的治疗至手术当日，存在呼吸功能损害的患者术前给予舒张气道药物。所有患者在手术室接受全身麻醉，监测生命体征手术时长和术中出血情况。术毕转入ICU，完善评分和实验室检查，给予抗感染、营养支持治疗，部分患者术后需机械通气。术后仍继续皮疹和呼吸功能治疗。
1.4. 资料采集
通过住院患者电子病例系统共获取符合纳入标准的68例患者的临床信息。本研究收集以下数据：患者人口学资料、既往病史、首发症状和诊断日期、皮肤和/或黏膜病变的类型和位置、各项相关免疫学指标、与天疱疮相关的实体肿瘤资料、外科术式、术中情况、术毕入ICU后各项数据、皮肤和外科切除标本病理结果、天疱疮相关治疗、预后。手术前皮损的严重程度依据天疱疮疾病面积指数(pemphigus disease area index, PDAI)评估，分数范围0~263分(皮肤活性120分，头皮活性10分，黏膜活性120分，炎症后色素沉着13分)，分数越高病损越严重[11]。电话随访患者家属，了解患者出院后的生存状况。
1.5. 统计学分析
根据随访结束时患者的生存情况，将所有患者分为生存组和死亡组。连续变量以均数±标准差(x±s)或中位数(四分位数)[M(Q1, Q3)]表示，分类变量以频数和百分比表示。对分类影响因素采用log-rank法进行单因素分析，采用1年、5年累积率对各组结局发生情况进行描述，对单因素和多因素均有统计学意义的指标绘制Kaplan-Meier生存曲线。采用单因素Cox比例风险模型对各影响因素进行分析，计算HR值及95%CI。将单因素分析中P＜0.10、分类下事件数＞5且排除共线性影响的因素纳入多因素Cox比例风险模型，采用向前法筛选预后因素并计算HR及95%CI。所有检验及变量筛选的检验水准均采用P < 0.05(双侧)。
2. 结果
2.1. 患者生存状况和一般临床资料
2005年1月1日至2020年12月31日期间共有符合纳入标准的68例患者。1例患者在接受手术前死亡。随访截止至2021年12月31日，4例患者失访，共63例患者资料进入统计。63例完成随访的患者平均年龄(41.7±16.2)岁，39.7%为男性，中位随访时间为95个月，25例患者(39.7%)在随访期间死亡，1年、3年、5年生存率分别为74.6%(95%CI 63.8%~85.4%)、67.4%(95%CI 55.6%~79.2%)和55.1%(95%CI 47.9%~62.3%)。完成随访的所有63例患者均为皮肤黏膜受损起病，口腔黏膜均有受累，有28例累及了生殖器和肛门黏膜，16例累及眼周黏膜；躯干及四肢皮损为红斑、囊泡、水疱、丘疹、糜烂、鳞屑等形式，其中累及躯干35例，累及四肢手足38例，以上多种皮肤黏膜损害可同时出现在一例患者身上。依据PDAI评分进行皮疹严重程度分级均为中度及以上。与存活者相比，死亡患者术前白蛋白更低、合并闭塞性细支气管炎更多，入ICU时氧合指数和白蛋白、血红蛋白浓度更低，入ICU后急性生理学及慢性健康状态评分(acute physiology and chronic health evaluation, APACHE Ⅱ)和序贯器官衰竭(sequential organ failure assessment, SOFA)评分更高，术后合并真菌感染更多，在ICU的机械通气时间和住院时间也更长(表 1)。
表 1.
患者一般临床资料
General clinical data of patients
| Items | Total (n=63) | Survivors (n=38) | Non-survivors (n=25) |
| Results are presented as mean ± SD (x±s), median (first quartile, third quartile) and numbers (%). Numbers in square brackets indicate the amount of missing values. BMI, body mass index; PNP, paraneoplastic pemphigus; CD, Castleman disease; PDAI, pemphigus disease area index; DSG, desmoglein; BP, bullous pemphigoid; BO, bronchiolitis obliterans; WBC, white blood cell; PaCO2, partial pressure of carbon dioxide in artery; OI, oxygenation index; Hgb, hemoglobin; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment; PCT, procalcitonin; MVT, mechanical ventilation time; ICU, intensive care unit; LHS, the length of hospital stay. | |||
| Baseline characteristics | |||
| Age/years, x±s | 41.7±16.2 | 39.6±16.3 | 46.8±14.8 |
| Age>40 years | 33 (52.4%) | 16 (42.1%) | 17 (68.0%) |
| Male | 25 (39.7%) | 16 (42.1%) | 9 (36.0%) |
| BMI /(kg/m2), x±s | 20.6±3.3 | 20.5±3.1 | 20.8±3.5 |
| Preoperative weight loss>5 kg | 41 (65.1%) | 20 (52.6%) | 21 (84.0%) |
| Preoperative comorbidities | 10 (15.9%) | 6 (15.8%) | 4 (16.0%) |
| Coronary heart disease | 5 (7.9%) | 3 (7.9%) | 2 (8.0%) |
| Hypertension | 7 (11.1%) | 6 (15.8%) | 1 (4.0%) |
| Diabetes | 3 (4.8%) | 1 (2.6%) | 2 (8.0%) |
| Cerebral infarction | 3 (4.8%) | 2 (5.3%) | 1 (4.0%) |
| Chronic bronchitis | 4 (6.3%) | 2 (5.3%) | 2 (8.0%) |
| Smoking | 4 (6.3%) | 2 (5.3%) | 2 (8.0%) |
| Preoperative albumin/(g/L), x±s | 30.9±4.7 | 32.3±3.7 | 26.8±5.0 |
| Preoperative data of PNP | |||
| Tumor location | |||
| Mediastinum | 31 (49.2%) | 17 (44.7%) | 14 (56.0%) |
| Lung | 1 (1.6%) | 1 (2.6%) | 0 (0.0%) |
| Abdominal cavity | 11 (17.5%) | 7 (18.4%) | 4 (16.0%) |
| Pelvis cavity | 8 (12.7%) | 5 (13.2%) | 3 (12.0%) |
| Post-peritonium | 10 (15.9%) | 7 (18.4%) | 3 (12.0%) |
| Multiple tumors | 2 (3.2%) | 1 (2.6%) | 1 (4.0%) |
| Pathological type | |||
| CD hyaline vascular | 40 (63.5%) | 26 (68.4%) | 14 (56.0%) |
| CD plasmacytic | 2 (3.2%) | 0 (0.0%) | 2 (8.0%) |
| CD mixed | 8 (12.7%) | 4 (10.5%) | 4 (16.0%) |
| Thymoma | 10 (15.9%) | 5 (13.2%) | 5 (20.0%) |
| Follicular dendritic cell sarcoma | 3 (4.8%) | 3 (7.9%) | 0 (0.0%) |
| Types of skin lesions | |||
| Erythema multiforme-like | 24 (38.1%) | 13 (34.2%) | 11 (44.0%) |
| Pemphigoid-like | 27 (42.9%) | 17 (44.7%) | 10 (40.0%) |
| Lichen planus-like | 6 (9.5%) | 4 (10.5%) | 2 (8.0%) |
| Pemphigus-like | 5 (7.9%) | 3 (7.9%) | 2 (8.0%) |
| Graft-versus-host disease-like | 1 (1.6%) | 1 (2.6%) | 0 (0.0%) |
| PDAI | |||
| Moderate (< 15 scores) | 19 (30.2%) | 12 (31.6%) | 7 (28.0%) |
| Significant (15-45 scores) | 13 (20.6%) | 7 (18.4%) | 6 (24.0%) |
| Extensive (>45 scores) | 31 (49.2%) | 19 (50.0%) | 12 (48.0%) |
| Serological biomarkers | |||
| DSG1(+) | 19 (46.3%) [22] | 8 (36.4%) [16] | 11 (57.9%) [6] |
| DSG3 (+) | 8 (17.0%) [22] | 3 (13.6%) [16] | 5 (26.3%) [6] |
| Antibodies of myasthenia gravis (+) | 10 (29.4%) [29] | 5 (23.8%) [17] | 5 (38.5) [12] |
| BP180 (+) | 26 (81.3%) [31] | 15 (83.3%) [20] | 11 (78.6%) [11] |
| Clinical complications of PNP | |||
| Dyspnea | 38 (60.3%) | 20 (52.6%) | 14 (56.0%) |
| BO | 28 (44.4%) | 11 (28.9%) | 17 (68.0%) |
| Myasthenia gravis | 7 (11.1%) | 4 (10.5%) | 3 (12.0%) |
| Preoperative bacterial pulmonary infection | 8 (12.7%) | 2 (5.3%) | 6 (24.0%) |
| Preoperative fungal infection | 4 (6.3%) | 1 (2.6%) | 3 (12.0%) |
| Treatment of PNP | |||
| Corticosteroids | 60 (95.2%) | 35 (92.1%) | 25 (100.0%) |
| Immunosuppressive agents | 5 (7.9%) | 2 (5.3%) | 3 (12.0%) |
| Gammaglobulin | 30 (47.6%) | 16 (42.1%) | 14 (56.0%) |
| Perioperative data | |||
| Onset-to-surgical excision time/month, M(Q1, Q3) | 5 (3, 10) | 5 (3, 11) | 4 (3, 8) |
| Surgical time/h, M(Q1, Q3) | 3.7 (2.3, 5.2) | 3.1 (2.0, 5.0) | 4.0 (3.0, 5.6) |
| Intraoperative bleeding volume/mL, M(Q1, Q3) | 300 (100, 850) | 300 (100, 500) | 300 (150, 1350) |
| Laboratory findings at ICU admission, x±s | |||
| WBC/(×109/L) | 8.9±3.5 | 8.6±3.4 | 9.3±3.6 |
| PaCO2/mmHg | 45±10 | 45±9 | 46±13 |
| OI/mmHg | 227±100 | 256±112 | 183±55 |
| Albumin/(g/L) | 25.0±4.2 | 26.2±3.8 | 23.2±4.3 |
| Hgb /(g/L) | 98.1±16.9 | 101.7±14.9 | 92.4±18.5 |
| Worst score in ICU | |||
| APACHE Ⅱ, M(Q1, Q3) | 8 (6, 12) | 7 (4, 8) | 10 (6, 13) |
| SOFA, M(Q1, Q3) | 2 (2, 3) | 2 (1, 3) | 3 (2, 3) |
| Postoperative infection | |||
| High PCT | 26 (50.0%) [11] | 12 (38.7%) [7] | 14 (66.7%) [4] |
| Fungal infection | 15 (23.8%) | 4 (10.5%) | 11 (44.0%) |
| Outcomes | |||
| MVT/h, M(Q1, Q3) | 14 (4, 67) | 9 (4, 23) | 23 (12, 86) |
| ICU stay/d, M(Q1, Q3) | 3 (1, 4) | 3 (1, 4) | 3 (1, 19) |
| LHS/d, M(Q1, Q3) | 34 (14, 67) | 22 (14, 42) | 49 (25, 79) |
| Follow-up time/m, M(Q1, Q3) | 95 (75, 132) | 92 (74, 132) | 114 (81, 130) |
| In-hospital deaths | 9 (14.3%) | 9 (36.0%) | |
| Post-discharge deaths | 16 (25.4%) | 16 (64.0%) | |
| Survival times/month, M(Q1, Q3) | 34 (1, 143) | 42 (32, 70) | 5 (2, 25) |
2.2. 预后的单因素分析
25例患者在研究期间死亡，主要原因是感染13例(52%)，呼吸衰竭7例(28%)，5例死亡原因不明。经log-rank检验，年龄＞40岁、体质量下降＞5 kg、术前白蛋白 < 30 g/L、合并闭塞性细支气管炎、术后存在真菌感染的患者，生存率有显著性差异(P＜0.05)。Cox单因素分析显示术前体质量下降>5 kg、白蛋白水平、术前合并闭塞性细支气管炎、肺部细菌感染、手术时间长、术后入ICU时氧合指数和白蛋白、血红蛋白浓度低、入ICU后APACHE Ⅱ评分、SOFA评分高，以及术后真菌感染都是影响远期存活的危险因素(P < 0.05，表 2)，对影响预后的分类变量绘制生存曲线见图 1。
表 2.
63例副肿瘤性天疱疮合并实体肿瘤患者总生存的单因素分析
Univariate analyses of overall survival in 63 patients with solid tumors complicated with paraneoplastic pemphigus
| Items | Survival rate/% | Log-rank | Cox univariate analysis | |||||
| 1 year | 5 years | χ 2 | P value | HR (95%CI) | P value | |||
| a, entered into the Cox model as continuous variable; b, the number of events is less than 5, so the Kaplan-Meier survival analysis were not performed; * P < 0.1. BMI, body mass index; PNP, paraneoplastic pemphigus; CD, Castleman disease; PDAI, pemphigus disease area index; DSG, desmoglein; BP, bullous pemphigoid; BO, bronchiolitis obliterans; ICU, intensive care unit; WBC, white blood cell; PaCO2, partial pressure of carbon dioxide in artery; OI, oxygenation index; Hgb, hemoglobin; APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment; PCT, procalcitonin. | ||||||||
| Baseline characteristics | ||||||||
| Age/years | 4.145 | 0.042* | ||||||
| ≤40 | 79.6 | 69.2 | 1 | |||||
| >40 | 69.7 | 41.1 | 2.23 (1.00-5.40) | 0.051* | ||||
| Gender | 0.344 | 0.558 | ||||||
| Female | 68.4 | 52.5 | 1 | |||||
| Male | 79.2 | 59.9 | 0.79 (0.35-1.78) | 0.563 | ||||
| Preoperative weight loss | 9.567 | 0.002* | ||||||
| ≤5 kg | 95.5 | 76.5 | 1 | |||||
| >5 kg | 63.0 | 43.7 | 4.77 (1.60-14.2) | 0.005* | ||||
| BMI/(kg/m2)a | 1.02 (0.90-1.15) | 0.815 | ||||||
| Preoperative comorbiditiesb | 1.14 (0.88-1.53) | 0.695 | ||||||
| Smokingb | 1.65 (0.71-2.40) | 0.237 | ||||||
| Preoperative data of PNP | ||||||||
| Preoperative albumin | 17.568 | < 0.001* | ||||||
| ≥30 g/L | 88.6 | 72.2 | 1 | |||||
| < 30 g/L | 55.6 | 26.7 | 5.62 (2.24-14.12) | < 0.001* | ||||
| Tumor location | 1.974 | 0.160 | ||||||
| Others | 80.6 | 61.5 | 1 | |||||
| Thoracic cavity | 68.5 | 50.4 | 1.76 (0.78-3.94) | 0.170 | ||||
| Pathological type | 0.028 | 0.866 | ||||||
| Others | 59.3 | 59.3 | 1 | |||||
| CD | 77.9 | 51.6 | 0.92 (0.34-2.47) | 0.868 | ||||
| Skin lesions type | 0.166 | 0.684 | ||||||
| Others | 74.3 | 51.3 | 1 | |||||
| Erythema multiforme-like | 74.8 | 52.2 | 1.50 (0.68-3.32) | 0.318 | ||||
| PDAI | 0.267 | 0.875 | ||||||
| Moderate (< 15 scores) | 63.6 | 53.0 | 1 | |||||
| Significant (15-45 scores) | 69.2 | 60.6 | 0.95 (0.38-2.43) | 0.922 | ||||
| Extensive (>45 scores) | 70.8 | 49.2 | 0.68 (0.22-2.05) | 0.490 | ||||
| Serological biomarkers | ||||||||
| DSG1 | 1.747 | 0.186 | ||||||
| DSG1 (-) | 77.3 | 57.5 | 1 | |||||
| DSG1 (+) | 68.4 | 33.2 | 1.82 (0.73-4.53) | 0.199 | ||||
| DSG3 | 2.744 | 0.254 | ||||||
| DSG3 (-) | 78.8 | 47.4 | 1 | |||||
| DSG3 (+) | 75.0 | 37.5 | 1.73 (0.62-4.83) | 0.297 | ||||
| BP180 (+)b | 0.59 (0.16-2.15) | 0.423 | ||||||
| Antibodies of myasthenia gravis | 3.710 | 0.054 | ||||||
| Antibodies of myasthenia gravis (-) | 71.6 | 55.7 | 1 | |||||
| Antibodies of myasthenia gravis (+) | 45.7 | 45.7 | 3.04 (0.92-10.06) | 0.069* | ||||
| Clinical complications of PNP | ||||||||
| Dyspnea | 2.816 | 0.093 | ||||||
| Without | 79.5 | 67 | 1 | |||||
| With | 71.1 | 46.2 | 0.75 (0.34-1.66) | 0.481 | ||||
| BO | 9.537 | 0.002* | ||||||
| Without | 82.5 | 72.8 | 1 | |||||
| With | 64.3 | 33.4 | 2.97 (1.31-6.75) | 0.009* | ||||
| Myasthenia gravisb | 2.49 (0.93-6.69) | 0.070* | ||||||
| Preoperative bacterial pulmonary infection | 3.171 | 0.074 | 2.62 (1.42-9.23) | 0.007* | ||||
| Without | 80.3 | 68.8 | ||||||
| With | 75.0 | 25.0 | ||||||
| Preoperative fungal infectionb | 2.05 (0.61-6.90) | 0.244 | ||||||
| Treatment of PNP | ||||||||
| Corticosteroidsb | 0.79 (0.18-3.41) | 0.753 | ||||||
| Immunosuppressive agentsb | 2.78 (0.82-9.41) | 0.100 | ||||||
| Gammaglobulin | 0.735 | 0.391 | ||||||
| Without | 78.7 | 56.4 | 1 | |||||
| With | 63.2 | 46.3 | 1.41 (0.64-3.10) | 0.399 | ||||
| Perioperative data | ||||||||
| Onset-to-surgical excision time/montha | 0.99 (0.95-1.04) | 0.668 | ||||||
| Surgical time/ha | 1.16 (1.00-1.33) | 0.048* | ||||||
| Intraoperative bleeding volume/mLa | 0.96 (0.66-1.38) | 0.943 | ||||||
| Laboratory findings at ICU admissiona | ||||||||
| WBC/(×109/L)a | 1.05 (0.94-1.18) | 0.407 | ||||||
| PaCO2/mmHga | 1.01 (0.97-1.05) | 0.620 | ||||||
| OI/mmHga | 0.99 (0.98-1.00) | 0.012* | ||||||
| Albumin /(g/L)a | 0.88 (0.80-0.97) | 0.010* | ||||||
| Hgb /(g/L)a | 0.97 (0.95-1.00) | 0.035* | ||||||
| Worst score in ICU | ||||||||
| APACHE Ⅱa | 1.25 (1.10-1.42) | 0.001* | ||||||
| SOFAa | 2.14 (1.20-3.82) | 0.010* | ||||||
| Postoperative infection | ||||||||
| PCT | 3.903 | 0.048 | ||||||
| Normal PCT | 80.6 | 60.4 | 1 | |||||
| High PCT | 57.2 | 37.5 | 2.41 (0.97-5.98) | 0.059* | ||||
| Fungal infection | 14.085 | < 0.001* | ||||||
| Without | 81.0 | 67.1 | 1 | |||||
| With | 53.3 | 16.0 | 6.03 (2.56-14.2) | < 0.001* | ||||
图 1.
患者的Kaplan-Meier生存曲线
Kaplan-Meier survival curve of patients
A, preoperative weight loss>5 kg and ≤5 kg (P=0.002); B, preoperative albumin < 30 g/L and ≥30 g/L (P < 0.001); C, with and without bronchiolitis obliterans (P=0.006); D, with and without postoperative fungal infection (P < 0.001). PNP, paraneoplastic pemphigus; BO, bronchiolitis obliterans.
2.3. 影响预后的多因素分析
将单因素分析中P＜0.10、事件数＞5的因素纳入多因素模型，其中APACHE Ⅱ评分因和SOFA评分共线性而排除，重症肌无力和重症肌无力抗体阳性因事件数≤5排除。使用向前法确定术前体质量下降＞5 kg(HR 4.44, 95%CI 1.47-13.38, P=0.008)、术前白蛋白＜30 g/L(HR 4.38, 95%CI 1.72-11.12, P=0.002)、术前合并闭塞性细支气管炎(HR 2.69, 95%CI 1.12-6.50, P=0.027)和术后真菌感染(HR 4.85, 95%CI 2.01-11.72, P < 0.001)是死亡风险增加的影响因素(表 3)。
表 3.
Cox多因素风险比例模型预测远期存活的影响因素
Multivariate analysis was performed using Cox proportional hazards model for various predictive factors
| Items | Univariate analysis P value | Multivariate analysis | |
| HR (95%CI) | P value | ||
| a, laboratory findings at the time of ICU admission. PNP, paraneoplastic pemphigus; BO, bronchiolitis obliterans; OI, oxygenation index; Hgb, hemoglobin; SOFA, sequential organ failure assessment; ICU, intensive care unit; PCT, procalcitonin. | |||
| Age>40 years | 0.051 | ||
| Preoperative weight loss>5 kg | 0.005 | 4.44 (1.47-13.38) | 0.008 |
| Preoperative albumin < 30 g/L | < 0.001 | 4.38 (1.72-11.12) | 0.002 |
| Antibodies of myasthenia gravis (+) | 0.069 | ||
| PNP with BO | 0.009 | 2.69 (1.12-6.50) | 0.027 |
| PNP with myasthenia gravis | 0.070 | ||
| Preoperative bacterial pulmonary infection | 0.007 | ||
| Surgical time/h | 0.048 | ||
| OI/mmHga | 0.012 | ||
| Albumin /(g/L)a | 0.010 | ||
| Hgb/ (g/L)a | 0.035 | ||
| Worst SOFA score in ICU | 0.010 | ||
| Postoperative high PCT | 0.059 | ||
| Postoperative fungal infection | < 0.001 | 4.85 (2.01-11.72) | < 0.001 |
3. 讨论
本研究收集了16年间副肿瘤性天疱疮合并Castleman病、胸腺瘤和滤泡树突细胞肉瘤等实体肿瘤、接受手术肿瘤切除术的重症病例，评估这类患者术后长期生存率的影响因素。文献报道，84%的副肿瘤性天疱疮继发于血液系统恶性肿瘤，与淋巴细胞增生相关[12]，其中与Castleman病相关的天疱疮占与血液肿瘤相关的副肿瘤性天疱疮病例的18.4%[13]，针对副肿瘤性天疱疮的预后研究结果差异性很大。中国最常见的副肿瘤性天疱疮相关肿瘤是Castleman病，占总数的77%[14]，这其中有大量病例存在实体肿瘤，而不同潜在肿瘤的副肿瘤性天疱疮患者治疗方法和预后均有不同，目前还没有文献专门评估副肿瘤性天疱疮合并实体肿瘤患者切除术后的预后。
本研究纳入的通过手术切除来治疗原发肿瘤的重症副肿瘤性天疱疮患者，具有皮疹进展速度快，皮损面积大、程度重，合并其他器官尤其呼吸系统受累等特征。常由于术中血流动力学不稳定、合并症多、闭塞性细支气管炎影响呼吸功能、术毕需要行机械通气, 以及围术期感染风险高而入ICU。这部分重症副肿瘤性天疱疮合并实体肿瘤的患者，预后和副肿瘤性天疱疮整体人群不同，预后影响因素也不一致。本研究中的1、3和5年生存率分别是74.6%、67.4%和55.1%，也证实了副肿瘤性天疱疮患者的预后通常较差。本研究中患者的生存期比以往针对全部副肿瘤性天疱疮患者和血液系统非实体瘤患者的研究明显更长，例如有文献研究了副肿瘤性天疱疮的1、2和5年生存率分别为49%、41%和38%[15]。近年随着治疗技术的发展，也有生存率更高的报道，1、3年生存率分别为76.9%和57.6%[16]。这种生存率上的差异可能取决于各研究针对的患者人群不同和治疗的差异。
由于皮损侵袭口腔、食道黏膜导致长期低营养摄入，患者倾向于表现出不同程度的体质量下降、电解质紊乱和低白蛋白血症，提示术前营养状态较差。多因素分析中也发现体质量下降和术前白蛋白水平与远期预后有关。在之前的研究中，研究者们主要着眼于疾病本身特征对于预后的影响，对于急性生理情况少有关注，没有研究指出低蛋白血症和预后的关系。本研究在营养状况方面做出了新的探索，提示如果在术前针对患者的营养缺乏状况进行白蛋白的补充、胃肠外营养支持，有可能改善患者的预后。
本研究中确诊闭塞性细支气管炎的患者占44.4%，其中有17例患者在5年内死亡。闭塞性细支气管炎的发病率在不同文献中差异很大，在Ouedraogo等[17]的研究中为25.7%；在近期Wang等[18]的研究中，全体副肿瘤性天疱疮患者闭塞性细支气管炎发病率在29%，但其中副肿瘤性天疱疮合并Castleman病患者闭塞性细支气管炎发病率为49%，与本研究结果相似。副肿瘤性天疱疮自身抗体介导的呼吸系统并发症，通常影响呼吸道黏膜[12]。副肿瘤性天疱疮的自身抗体会沉积在支气管上皮，导致角化不良和支气管上皮细胞棘溶，从固有层和邻近细胞分离。病变细支气管的管腔变得严重狭窄，逐渐发展为闭塞性细支气管炎。患者即使在治疗原发肿瘤后，仍有可能存在肺部病变进展，是由于病变的细支气管上皮继续损害，加重管腔狭窄和阻塞，最终死于呼吸衰竭和肺部感染，造成副肿瘤性天疱疮患者高死亡率[10, 13]。本研究中闭塞性细支气管炎是死亡的独立危险因素，目前的治疗手段仅为针对存在呼吸系统症状的患者进行对症支持，治疗手段包括口服氨茶碱及发作喘憋时加用静脉茶碱类药物，吸入支气管扩张药物包括β2受体激动剂、抗胆碱药和磷酸二酯酶抑制剂以及吸入糖皮质激素，这些治疗只能改善症状，但无法干预闭塞性细支气管炎的病程进展，并不影响患者的最终结局。本研究中术毕转入ICU后，有84.1%的患者需要继续进行机械通气。提示临床医师应该在术前即评估患者的肺功能和血气分析指标，并积极预防在术后闭塞性细支气管炎继续进展。
副肿瘤性天疱疮的大量皮损类似于全身烧伤的病理状态，在治疗中还会造成免疫功能低下，这些会增加严重感染的风险[19]。本研究中很多患者术前即存在感染，大部分是皮损处感染，少量存在肺部感染。在术前皮损感染的患者中，仅体温升高的患者接受抗生素治疗，而术前已存在肺部感染的患者全部接受抗生素治疗。术后降钙素原增高的患者占半数，还有部分患者确诊真菌感染。术后所有患者均接受抗生素治疗，术后预防使用抗生素为二代头孢、三代头孢和喹诺酮类药物，针对术后细菌感染使用的抗生素包括三代头孢联合酶抑制剂、碳青霉烯类、糖肽类及利奈唑胺、多粘菌素、替加环素，针对真菌感染使用棘白菌素类和三唑类抗真菌药。在多因素分析中发现，只有术后真菌感染是死亡的独立危险因素。副肿瘤性天疱疮患者常需要长时间使用激素治疗皮损和肺部并发症，并针对细菌感染使用广谱抗生素，这都是导致真菌感染的原因。研究结果提示真菌感染对于患者来说更加致命，防治真菌感染可能会改善患者的预后。
本研究发现皮损的程度范围、类型与死亡率并无明显相关性，也未发现副肿瘤性天疱疮相关的免疫指标与生存率的关系。另外，从发病到切除肿瘤的时间长短对死亡率也并无影响。这些与文献报道的副肿瘤性天疱疮的发展过程并不平行于肿瘤的进展相一致[7]。早期发现和完全切除肿瘤是至关重要的，是获得较好结果的先决条件。但是副肿瘤性天疱疮的预后取决于潜在恶性肿瘤的性质和严重呼吸衰竭的进展。副肿瘤性天疱疮患者即使在肿瘤已得到治疗的情况下，皮损仍可能进展，小气道破坏、肺纤维化和阻塞性肺病不可逆，同时肺部感染风险高，严重影响了预后。
本研究存在一定的局限性，为单中心回顾性研究，且因研究对象为罕见病，样本量较小，终点事件数较少，可能会影响统计模型的效率。部分实验室检查和免疫学检查数据缺失，可能会影响结果的可靠性。针对这种罕见病的其他研究也存在样本量较少，经常只有描述性研究的问题，我们将持续关注这类疾病，积累病例数。
综上，本研究对63例合并实体肿瘤、接受手术治疗的副肿瘤性天疱疮患者进行了中位时间为95个月的随访，术后5年存活率约为55.1%。多因素分析提示术前体质量下降＞5 kg、术前低白蛋白血症、术前合并闭塞性细支气管炎和术后并发真菌感染是这类患者术后死亡的危险因素。如何通过围术期管理以进一步改善此类患者预后值得进一步研究。
Biography
李双玲，主任医师，副教授，硕士研究生导师，博士，现任北京大学第一医院重症医学科常务副主任。主要研究方向：危重患者急性肾损伤发生危险因素及预测模型，人羊膜上皮细胞治疗脓毒症急性肾损伤；危重患者机械通气时镇静对于谵妄和睡眠的影响；脓毒症血流感染诊断和预后评估、腹腔真菌感染诊断新技术等。已在中文核心期刊发表论文30余篇，SCI论文10余篇。现主持中国卫生信息与健康医疗大数据学会重症感染镇痛镇静大数据专项研究，中央高水平医院临床科研跨学科交叉研究专项“基于双层微孔阵列滤膜预处理实时荧光定量聚合酶链式反应检测诊断重症医学科腹腔念珠菌感染的多中心前瞻性队列研究”，作为分中心负责人现主持国家科技部“主动健康和老龄化科技应对”重点研发计划中的子课题“建立老年血流感染的防控体系”、首都卫生发展科研专项“抗Xa监测危重患者低分子肝素预防静脉血栓栓塞症的随机对照试验研究”等。任职中国医师协会重症医学会委员、北京医师协会重症医学专科医师分会常务理事、北京医学会重症分会委员、北京生理学会危重病专业委员会副主任委员、北京抗癌协会肿瘤重症专业委员会副主任委员、中国人体健康科技促进会重症医学与器官支持专业委员会常务委员、北京重症超声研究会副秘书长等
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